The present invention is directed to novel isoxazole compounds, methods for their preparation, pharmaceutical compositions comprising these compounds, and their use in therapy, particularly in the prevention and/or treatment of disease states associated with immune cell activation and proliferation.
Higher organisms are characterized by an immune system which protects them against foreign pathogens and endogenous diseases such as tumors and genetic defects. The immune system has developed a series of pathways to protect the host. The primary cells of the immune system are lymphocytes. One class of lymphocytes, T lymphocytes, affects and regulates the cell mediated response of the immune system. They consist of a heterogeneous population of cells with several distinct functional subsets called helper cells, suppressor cells and killer cells.
T lymphocytes are derived from the thymus and circulate through the blood and lymphatic vessels of the body where they can detect and interact with foreign invaders i.e. viruses, allergens, tumors and autoantigens. Upon specific interaction with invading pathogens,
T lymphocytes are activated, resulting in the development of enlarged cellsxe2x80x94T cell blastsxe2x80x94which subsequently turn on the machinery for cytokine synthesis, cytokine receptor expression and proliferation. This initiates a cascade of host defense actions involving other lymphocyte subsets.
While the normal immune system is closely regulated, aberrations in the immune response are not uncommon. Many signs and symptoms of infectious, inflammatory and neoplastic diseases evolve as a result of abnormalities in the immune system, especially in T lymphocyte-mediated immunity. Even if these immunocompetent cells are not involved in the initial stage, abnormal regulation of otherwise normal appropriate cellular immune reactions may lead to acute and chronic diseases. These diseases are often of unknown etiology and include systemic rheumatic diseases, organ specific endocrine diseases, inflammatory disease of the gut and skin. The treatments available in relation to said diseases are usually symptomatic or palliative, i.e. most of the drugs prescribed in connection with said diseases are directed at allaying the symptoms and have no curative effect. Thus, a long-felt need exists for an effective means of curing or ameliorating T lymphocyte-mediated pathologies. Such a treatment should ideally control the inappropriate T cell response, rather than merely reducing the symptoms.
Current treatments of immunoinflammatory and proliferative diseases involve the administration of drugs which suppress the immune response. Examples of such drugs include methotrexate, cyclophosphamide, azathioprine, rapamicine, cyclosporin A, FK-506 and leflunomide. The use of these drugs is limited due to the cytotoxic effect (gastrointestinal symptoms, nefro- and hepatotoxicity) on the host and also because they induce global immunosuppression. For example, prolonged treatment with these drugs can lead to infections and malignancies. Steroid compounds like corticosteroids (prednisolone, deflazacort) are also employed in many instances. Although some efficacy of corticosteroids in immunoinflammatory diseases was demonstrated, their long term adverse effects, particularly osteoporosis, have remained a substantial obstacle limiting their routine use.
A more selective therapeutic approach involves the use of antibodies or soluble receptors directed to T cell markers (e.g. CD4, CD8, B7, T cell receptor) or to cytokines involved in the disease (e.g. IL-1, IL-2, TNF-xcex1) or their receptors. These alternatives are associated with high production costs. Another proposed therapy involves the induction of tolerance by the oral administration of the antigen which is related to the cause of the disease. However, use of this therapeutic modality is limited due to the difficulty in identifying and purifying the antigen(s) responsible for the autoimmune disease afflicting the patient.
Thus, new compounds with improved therapeutic activity and reduced side effects are needed.
Accordingly, the present invention provides certain isoxazole derivatives having the formula 
wherein m, n and p are each independently 0 or 1 and q is 0, 1, 2, 3, 4 or 5; xe2x80x94A1xe2x95x90A2xe2x80x94A3xe2x95x90A4xe2x80x94 is a bivalent radical of formula
xe2x80x83xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-1)
xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-2)
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-3)
xe2x80x94CHxe2x95x90CHxe2x80x94Nxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-4)
xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-5)
xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-6)
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-7)
B is a bivalent radical of formula 
D is Ar1 or Het1;
Q is a direct covalent bond or a bivalent radical of formula 
wherein
X1 and X2 are each independently S or O, t is 0, 1 or 2;
X3 is independently S, O or NR26; X4 and X5 are each independently N or CH.
L is Ar1 or Het1;
R1 is selected from hydrogen, halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(3-6)cycloalkenylC((1-6)alkyl, C(3-6)cycloalkyloxy, haloC((1-6)alkyl, cyano, guanidine, nitro and NR17R18;
R2 and R3 are each independently selected from hydrogen, halo, C(1-6)alkyloxy and C(1-6)alkyl where the alkyl moiety may be optionally substituted by one or more hydroxy [for example 1, 2 or 3];
R4 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl and
C(3-6)cycloalkenyl;
R5, R6, R9 and R10 are each independently selected from hydrogen, hydroxy, halo, C(1-6)alkyl, [where the alkyl moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR17R18, (SO2)R16, (Cxe2x95x90O)R16, Ar1 and Het1], C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo C(1-6)alkyloxy, (xe2x95x90O), NR17R18, (SO2)R16, (Cxe2x95x90O)R16, Ar1 and Het1], cyano, (Cxe2x95x90O)R25, (Cxe2x95x90O)OR16, (SO2)R16, aminocarbonyloxy, aminoC(1-6)alkyl, NR17R18, N3, Ar1 and Het1;
or
R5 and R6 and R10 together with the carbon atom to which they are attached, form a Het1 or a C(2-14) carbocyclic radical optionally substituted by 1,2 or 3 substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR23R24, (Cxe2x95x90O)R22, C(6-14)aryl and C(1-14)heterocycle], cyano, (xe2x95x90O), (xe2x95x90NH), (Cxe2x95x90O)R22, (SO2)R22, NH(Cxe2x95x90O)R22, NR23R24, C(6-14)aryl, C(6-14)aryl-thio, C(6-14)aryloxy [where the aryloxy moiety may be optionally substituted by halo] and C(1-14)heterocycle;
R7 and R8 are each independently selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, hydroxyC(1-6)alkyl and C(1-6)alkyloxy;
R11 is selected from hydrogen, hydroxy and C(1-6)alkyloxy [where the alkyloxy moiety may be optionally substituted by (Cxe2x95x90O)R16];
R12 is selected from hydrogen and hydroxy;
R13 is selected from hydrogen, hydroxy, halo, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, (xe2x95x90O), NR17R18, (SO2)R16, (Cxe2x95x90O)R16, Ar1 and Het1], aminocarbonyloxy, amino(C(1-6)alkyl, NR17R18, N3, Ar1 and Het1;
R14 and R15 are each independently selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(3-6)cycloalkyl, C(1-6)alkyloxy, cyano, (Cxe2x95x90O)R16, Ar1 and Het1], C(6-14)arylC(1-6)alkyl, (Cxe2x95x90)R16, (Cxe2x95x90O)OR16, (Cxe2x95x90S)R16, (SO2)R16, Ar1 and Het1;
or
R14 and R15 together with the N atom to which they are attached, form a C(1-14)heterocycle optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl and C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxy, (Cxe2x95x90))R16, Ar1 and Het1], C(6-14)arylthio, C(6-14)aryloxy, cyano, (Cxe2x95x90O)R16, (Cxe2x95x90O)OR16, (SO2)R16, NR17R18, Ar1 and Het1;
R16 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxycarbonyl, NR17R18, Ar1 and Het1], NR17R18, C(6-14)aryloxy, Ar1 or Het1;
R17 and R18 are each independently selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(3-6)cycloalkyl, C(1-6)alkyloxy, (Cxe2x95x90O)R19, Ar1 and Het1], (Cxe2x95x90O)R19, (SO2)R19, Ar1 and Het1;
or
R17 and R18 together with the N atom to which they are attached, form a C(1-14)heterocycle optionally substituted by 1,2 or 3 substituents independently selected from hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(1-6)alkyloxy, (Cxe2x95x90O)R19, Ar1 and Het1], NR20R21, (Cxe2x95x90O)R19, (xe2x95x90NH), Sxe2x80x94Ar1, Ar1 and Het1;
R19 is selected from C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, (Cxe2x95x90O)R22, NR20R21, Ar1 and Het1], phenyloxy, NR20R21, Ar1 and Het1;
R20 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, NH(Cxe2x95x90O)R22 and C(1-6)alkyloxy;
R21 is selected from hydrogen, hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(1-6)alkyloxycarbonyl, Ar1 and Het1;
Ar1 is a C(1-14)aryl (or C(6-14)arylidene when D is Ar1) optionally substituted by one or more substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR23R24, (Cxe2x95x90O)R22, C(6-14)aryl and C(1-14)heterocycle], cyano, (xe2x95x90O), (xe2x95x90NH), (Cxe2x95x90O)R22, (SO2)R22, NH(Cxe2x95x90O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy [where the aryloxy moiety may be optionally substituted by halo] and C(1-14)heterocycle;
Het1 is a C(1-14)heterocycle (or C(1-14)heterocyclidene when D is Het1) optionally substituted by one or more substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR23R24, (Cxe2x95x90O)R22, C(6-14)aryl and C(1-14)heterocycle], cyano, (xe2x95x90O), (xe2x95x90NH), (Cxe2x95x90O)R22, (SO2)R22, NH(Cxe2x95x90O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy [where the aryloxy moiety may be optionally substituted by halo] and C(1-14)heterocycle;
R22 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(1-6)alkyloxy, haloC(1-6)alkyl, NR23R24 and 
R23 and R24 are each independently selected from hydrogen, C(1-6)alkyl and 
R25 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxycarbonyl, NR17R18, Ar1 and Het1], C(6-14)aryloxy, Ar1 and Het1;
R26 is selected from hydrogen, C(1-6)alkyl and phenyl;
or a N-oxide, addition salt, quaternary amine or stereochemically isomeric form thereof;
A special group of compounds are those compounds of formula (I) wherein Q is a bivalent radical of formula (c-1), (c-2), (c-3), (c-4), (c-5), (c-6), (c-7), (c-8), (c-9), (c-10), (c-11) or (c-12).
Further, suitable compounds of formula (I) include those wherein xe2x80x94A1xe2x95x90A2xe2x80x94A3xe2x95x90A4xe2x80x94 is a radical of formula (a-1), (a-2), (a-3), (a-4), (a-5) or (a-6).
According to a further aspect the present invention provides compounds of formula (I) wherein:
m is 0 or 1;
n is 0;
p is 0 or 1;
q is 0, 1, 2 or 3;
xe2x80x94A1xe2x95x90A2xe2x80x94A3xe2x95x90A4xe2x80x94 is a radical of the formula (a-1), (a-2), (a-3), (a-4), (a-5), (s-6) or (a-7), preferably (a-1), (a-2), (a-3), (a-4), (a-5) or (a-6);
D is selected from pyridinylidene and phenylidene [where the phenylidene moiety is optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyl, C(1-6)alkyloxy, phenylC(1-3)alkyloxy, haloC(1-6)alkyl and (Cxe2x95x90O)R16];
L is selected from phenyl [where the phenyl moiety is optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyl, aminoC(1-6)alkyl, haloC(1-6)alkyl, C(1-6)alkyloxy, NR17R18, (SO2)R19 and NH(Cxe2x95x90O)R22], phenylcarbonyl, naphthyl and C(1-14)heterocycle [where the heterocycle moiety is optionally substituted by one or more substituents independently selected from C(1-6)alkyl, C(1-6)alkyloxy, C(1-6)alkyloxycarbonyl and NR23R24];
R1 is selected from hydrogen, halo, C(1-6)alkyl, C(1-6)alkyloxy, C(3-6)cycloalkyloxy, haloC(1-6)alkyl, cyano, nitro and hydroxy;
R2 is selected from hydrogen and C(1-6)alkyloxy;
R3 is hydrogen;
R4 is selected from hydrogen and C(1-6)alkyl [where the alkyl moiety may be optionally substituted by hydroxy];
R5 is selected from hydrogen, hydroxy, C(1-6)alkyl and cyano;
R6 is selected from hydrogen, hydroxy, C(1-6)alkyl [where the alkyl moiety may be optionally substituted by one or more substituents independently selected from NR17R18 and C(1-14)heterocycle (where the heterocycle moiety is optionally substituted by C(1-6)alkyl)], C(2-6)alkynyl, C(1-6)alkyloxy [where the alkyloxy moiety may be optionally substituted by C(1-6)alkyloxy], (Cxe2x95x90O)R16, aminocarbonyloxy, N3, phenyl [where the phenyl moiety may be optionally substituted by halo] and C(1-14)heterocycle [where the heterocycle moiety is optionally substituted by one or more substituents independently selected from NR23R24 and phenyl];
or
R5 and R6 together can form 1,3-dioxolanyl;
R7, R9 and R10 are hydrogen;
R8 and R13 are each independently selected from hydrogen and C(1-6)alkyl;
R11 is selected from hydroxy and C(1-6)alkyloxy [where the alkyloxy moiety may be optionally substituted by (Cxe2x95x90O)NR17R18];
R12 is selected from hydrogen and hydroxy;
R14 is selected from hydrogen and C(1-6)alkyl;
R15 is selected from hydrogen, C(1-6)alkyl [where the alkyl moiety may optionally be substituted by one or more substituents independently selected from C(1-6)alkyloxy, C(3-6)cycloalkyl and C(1-14)heterocycle], C(1-6)alkyloxy, phenyl and C(1-14)heterocycle [where the heterocycle moiety is optionally substituted by one or more substituents independently selected from hydroxy, C(1-6)alkyl, C(1-6)alkyloxy, C(1-6)alkyloxycarbonyl, (SO2)R19 and C(1-14)heterocycle];
or
R14 and R15 together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring optionally substituted by 1,2 or 3 substituents independently selected from phenyl, phenylC(1-6)alkyl and (Cxe2x95x90O)R16;
R16 is selected from hydrogen, hydroxy, C(1-6)alkyl [where the alkyl moiety may be optionally substituted by one or more substituents independently selected from halo, NR17R18, phenyl and Het1], C(1-6)alkenyl, phenylC(2-6)alkenyl, C(1-6)alkyloxy, fluoreneC((1-6)alkyloxy, phenyloxy, NR17R18, Ar1 and Het1;
R17 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(3-6)cycloalkyl, C(1-6)alkyloxy-C(1-6)alkyl, aminocarbonylC(1-6)alkyl and (Cxe2x95x90O)R19;
R18 is selected from hydrogen, C(1-6)alkyl [where the alkyl moiety may be optionally substituted by one or more substituents independently selected from C(3-6)cycloalkyl, (Cxe2x95x90O)R19, Ar1 and Het1], C(2-6)alkynyl [where the alkynyl moiety may be optionally substituted by phenyl], C(3-6)cycloalkyl, (Cxe2x95x90O)R19, (SO2)R19, Ar1 and Ht1;
or
R17 and R18 together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring optionally substituted by 1, 2 or 3 substituents independently selected from hydroxy, C(1-6)alkyl [where the alkyl moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(1-6)alkyloxy, (Cxe2x95x90O)R19, Ar1 and Het1], C(3-6)cycloalkyl, amino, (Cxe2x95x90O)R19, Sxe2x80x94Ar1, Ar1 and Het1;
R19 is selected from C(1-6)alkyl [where the alkyl moiety may be optionally substituted by one or more substituents independently selected from halo, phenyl, C(1-6)alkyloxycarbonyl, NR20R21 and Het1], C(2-6)alkynyl [where the alkynyl moiety may be optionally substituted by phenyl], C(1-6)alkyloxy, fluoreneC(1-6)alkyloxy, phenyloxy, amino, Ar1 and Het1;
R20 is selected from hydrogen and C(1-6)alkyl;
R21 is a selected from hydrogen, C(1-6)alkyl, C(3-6)cycloalkyl, C(1-6)alkyloxycarbonyl, phenyl and Het1;
Ar1 is a C(6-14)aryl substituted by one or more substituents independently selected from halo, cyano, C(1-6)alkyl, C(1-6)alkyloxy, phenylC((1-6)alkyloxy, phenyloxy, halophenyloxy, haloC(1-6)alkyl and (Cxe2x95x90O)R22, (SO2)R22, NH(Cxe2x95x90O)R22 and NR23R24;
Het1 is a C(1-14)heterocycle substituted by one or more substituents independently selected from hydroxy, C(1-6)alkyl, phenylC(1-6)alkyl, aminoC(1-6)alkyl, C(1-6)alkylaminoC(1-6)alkyl, (xe2x95x90O), (xe2x95x90NH), NH(Cxe2x95x90O)R22, NR23R24 and phenyl;
R22 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(1-6)alkyloxy, haloC(1-6)alkyl, NR23R24 and 
R23 and R24 are each independently selected from hydrogen, C(1-6)alkyl and 
or a N-oxide, addition salt, quaternary amine or stereochemically isomeric form thereof;
As used herein C(1-3)alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, and the like; C(1-4)alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the groups defined for C(1-3)alkyl, butyl, isopropyl and the like, C(1-6)alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C(1-4)alkyl and pentyl, hexyl, 2-methylpropyl, 2-methylbutyl and the like; C(3-6)cycloalkyl is generic to cyclo-propyl, cyclobutyl, cyclopentyl and cyclohexyl; C(2-3)alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 3 carbon atoms containing a double bond, such as ethenyl or propenyl; C(2-4)alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 4 carbon atoms containing a double bond, such as the groups defined for C(2-3)alkenyl and butenyl, C(2-6)alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a double bond such as the groups defined for C(2-4)alkenyl and pentenyl or hexenyl, C(3-6)cycloalkenyl is generic to cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. As used herein the term C(2-3)alkynyl defines straight and branched chain hydrocarbon radicals having 2 to 3 atoms containing a triple bond, such as ethynyl or propynyl; C(2-6)alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a triple bond such as the groups defined for C(2-3)alkynyl and butynyl, pentynyl or hexynyl. The term C(1-3)alkyloxy defines straight or branched chain saturated hydrocarbon radicals such as methoxy, ethoxy, or propyloxy. C(1-6)alkyloxy defines straight or branched chain saturated hydrocarbon radicals such as the groups defined for C(1-3)alkyloxy and butyloxy, pentyloxy, hexyloxy, 1-methylethyloxy, 2-methylpropyloxy, 2-methylbutyloxy and the like; C(3-6)cycloalkyloxy is generic to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
As used herein before, the term (xe2x95x90)) forms a carbonyl moiety with the carbon atom to which it is attached. The term (xe2x95x90NH) forms a imino moiety with the carbon atom to which it is attached.
The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, haloC(1-6)alkyl is defined as mono- or polyhalosubstituted C(1-6)alkyl, in particular C(1-6)alkyl substituted with one or more fluor atoms, for example trifluoromethyl.
The term C(6-14)aryl as a group or part of a group defines carbocyclic radicals containing one or more rings which may be independently saturated, partially saturated or unsaturated. The term covers fused ring systems as well as systems which are connected through a linking group, e.g. xe2x80x94Nxe2x80x94, xe2x80x94Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or a bond. Examples of such groups are phenyl, biphenyl, fluorenyl or naphthyl. C(6-14)arylidene is a bivalent C(6-14)aryl radical as described supra.
The term C(2-14)carbocyclic radical as a group or part of a group defines carbocyclic radicals containing one or more rings (including 3, 4, 5 or 6 membered carbocyclic rings) which may be independently saturated, partially saturated, unsaturated, including aromatic. The term covers fused ring systems as well as systems which are connected through a linking group, e.g. xe2x80x94Nxe2x80x94, xe2x80x94Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or a bond.
The term C(1-14)heterocycle defines one or more rings (including 3, 4, 5 or 6 membered heterocyclic rings) which may be independently saturated, partially saturated, unsaturated, including aromatic, containing one or more (for example 1, 2, 3 or 4) heteroatoms selected from N, O and S. Examples of such groups include indanyl, pyridinyl, tetrahydropyridinyl isothiazolyl, pyrrolyl, triazolylphenyl, piperidinyl, thiazolyl, piperazinyl, isoxazolyl, pyrazolyl, morpholinyl, imidazolyl, oxadiazolyl, dioxolanyl, pyrimidinyl, dihyropyrimidinyl, oxazolidinyl, benzimidazolyl, benzothiazolyl, benzodioxolanyl, benzopyridinyl, benzopyranyl, furanyl, thionyl, triazospirodecanyl, isoquinolinyl or tetrazolyl. C(1-14)heterocylidene is a bivalent C(1-14)heterocyclic radical as described supra.
As used herein before, the term xe2x80x9cone or morexe2x80x9d covers the possibility of all the available C-atoms, where appropriate, to be substituted, preferably 1, 2 or 3.
Het1 is meant to include all the possible isomeric forms of the heterocycles mentioned in the definition of Het1 for instance, pyrrolyl also includes 2H-pyrrolyl, pyranyl includes 2H-pyranyl and 4H-pyranyl.
The C(1-14)heterocycle represented by Het1 may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-traizol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when it is benzthiazolyl, it may be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl.
When any variable (eg. Ar, Het, R1, R2 etc.) occurs more than one time in any constituent, each definition is independent.
Lines drawn into ring systems from substituents indicate that the bond may be attached to any of the suitable ring atoms.
It will be appreciated that some of the compounds of formula (I) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salts, solvates or quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
Compounds of formula (I) as defined supra of particular interest include those where the asymmetric carbon atom indicated with an * has an S-configuration.
For some of the compounds of formula (I), their N-oxides, salts, solvates or quaternary amines and the intermediates used in the preparation thereof, the absolute stereochemical configuration was not experimentally determined. In these cases the stereoisomeric form which was first isolated is designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d, without further reference to the actual stereochemical configuration. However, said xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d stereoisomeric forms can be unambiguously characterized by for instance their optical rotation in case xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d have an enantiomeric relationship. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction. In case xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d are stereoisomeric mixtures, they can be further separated whereby the respective first fractions isolated are designated xe2x80x9cA1xe2x80x9d and xe2x80x9cB1xe2x80x9d and the seconds as xe2x80x9cA2xe2x80x9d and xe2x80x9cB2xe2x80x9d, without further reference to the actual stereochemical configuration.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butane-dioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, when an aromatic heterocyclic ring is substituted with hydroxy the keto-form may be the mainly populated tautomer.
Preferred embodiments of the present invention include compounds of formula (I) wherein one or more of the following restrictions apply:
(i) B is a group of formula (b-2);
(ii) xe2x80x94A1xe2x95x90A2xe2x80x94A3xe2x95x90A4xe2x80x94 is a radical of formula (a-1);
(iii) groups R1, R2, R3 and R4 are hydrogen;
(iv) m and n are 0 and p is 0 or 1;
(v) D is Ar1 [wherein Ar1 is preferably phenylidene (wherein the phenylidene moiety may be optionally substituted with halo)] or Het1 [wherein Het1 is preferably pyridinylidene];
(vi) L is Ar1 [wherein Ar1 is most preferably phenyl {wherein the phenyl moiety may be optionally substituted with one or more substituents, preferably 1, 2 or 3 substituents, independently selected from halo, C(1-3)alkyloxy, C(1-3)alkyl (wherein the alkyl moiety may be optionally substituted with one or more halo, preferably substituted with 3 F substituents), NR23R24 (wherein R23 and R24 are preferably independently selected from hydrogen and C(1-3)alkyl), (Cxe2x95x90O)R22 (wherein R22 is preferably NR23R24 (wherein R23 and R24 are preferably independently selected from hydrogen and C(1-3)alkyl)), (SO2)R22 (wherein R22 is preferably C(1-3)alkyl (wherein the alkyl moiety may be optionally substituted with one or more halo)) and NH(Cxe2x95x90O)R22 (wherein R22 is preferably 
or naphtalenyl] or Het1 [wherein Het1 is preferably selected from pyridinyl, furanyl, thiophenyl, benzodioxolanyl, quinolinyl and 1,3,4H-isoquinolinyl (wherein the 1,3,4H-isoquinolinyl moiety may be optionally substituted with one or more, preferably 1 or 2 C(1-3)alkyloxy)];
(vii) Q is preferably a bivalent radical of formula (c-1), (c-2), (c-3), (c-4), (c-5), (c-6), (c-7), (c-8), (c-9) or (c-10), most preferably, Q is a bivalent radical of formula (c-1), (c-3), (c-4), (c-5), (c-7) or (c-10).
When
1. Q is (C-2), X1 is preferably S or O;
2. Q is (c-3), R5 is preferably selected from hydrogen, hydroxy and cyano;
R6 is preferably selected from hydrogen, hydroxy, (Cxe2x95x90))OR16, NR17R18, N3, C(1-3)alkyl [wherein the alkyl moiety may be optionally substituted with (xe2x95x90O), NR17R18,
C(1-3)alkyloxy, Ar1 (wherein Ar1 is preferably phenyl) or Het1 (wherein Het1 is preferably pyridinyl)], C(1-3)alkyloxy [wherein the alkyloxy moiety may be optionally substituted with (xe2x95x90)), NR17R18, C(1-3)alkyloxy or Ar1 (wherein Ar1 is preferably phenyl)], Ar1 [wherein Ar1 is preferably phenyl] and Het1 [wherein Het1 is preferably pyridinyl or thiazolyl (wherein the thiazolyl may be optionally substituted with one or two substituents independently selected from amino and phenyl)];
R16 is preferably C(1-3)alkyl;
R17 is preferably hydrogen;
R18 is preferably selected from hydrogen, C(3-6)cycloalkyl, (Cxe2x95x90O)R19, C(1-3)alkyl [wherein the alkyl moiety is optionally substituted by (Cxe2x95x90O)R19 or Het1 {wherein Het1 is preferably benzimidazolyl (wherein the benzimidazolyl is preferably substituted with C(1-3)alkyl), piperidine (wherein the piperidine is preferably substituted with C(1-3)alkyl), pyridinyl, morpholinyl or 1,2-dioxolanyl}], Ar1 [wherein Ar1 is preferably phenyl {wherein the phenyl moiety is optionally substituted by one or more substituents, preferably 1, 2 or 3 substituents, independently selected form halo, hydroxy, C(1-3)alkyloxy, (Cxe2x95x90O)R22, NH(Cxe2x95x90O)R22, (SO2)R22, C(1-3)alkyl (wherein the alkyl moiety is optionally substituted by one or more halo), and Het1 (wherein Het1 is preferably piperidinyl)] and Het1 [wherein Het1 is preferably selected from pyridinyl, benzitriazolyl, benzimidazolyl (wherein the benzimidazolyl is preferably substituted with C(1-3)alkyl), piperidinyl (wherein the piperidinyl moiety is preferably substituted with C(1-3)alkyl, C(1-3)alkylphenyl) or isoxazolyl (wherein the isoxazolyl is preferably substituted with C(1-3)alkyl)];
or
R17 and R18 together with the N atom to which they are attached preferably form an optionally substituted C(1-14)heterocycle, preferably 2H-pyridine [wherein the 2H-pyridine is preferably substituted with (xe2x95x90NH)], morpholinyl,
1,3,4H-isoquinolinyl, piperidine [wherein the piperidine is preferably substituted with C(1-3)alkyl (wherein the alkyl moiety may be optionally substituted with N-methylpiperazinyl) or piperidine];
R19 is preferably selected from C(1-3)alkyl [wherein the alkyl moiety may be optionally substituted with NR20R21, Ar1 (wherein Ar1 is preferably phenyl)], NR20R21 and Ar1 [wherein Ar1 is preferably phenyl (wherein the phenyl moiety is optionally substituted by one or more halo)];
R20 is preferably selected from hydrogen and C(1-3)alkyl;
R21 is preferably selected from hydrogen and Het1 [wherein Het1 is preferably piperidinyl (wherein the piperidinyl moiety is preferably substituted with C(1-3)alkyl)];
R22 is preferably selected from C(1-3)alkyl and NR23R24;
R23 is preferably hydrogen;
R24 is preferably hydrogen;
3. Q is (c-4), R7 is preferably hydrogen;
4. Q is (c-5), R8 is preferably hydrogen;
5. Q is (c-6), R9 and R10 are preferably hydrogen;
6. Q is (c-7), R11 is preferably selected from hydroxy and C(1-3)alkyloxy [wherein the alkyloxy moiety may be optionally substituted with (Cxe2x95x90O)R16];
R16 is preferably NR17R18;
R17 is preferably C(1-3)alkyl;
R18 is preferably C(3-6)cycloalkyl;
7. Q is (c-8), t is preferably 1;
R12 is preferably selected from hydrogen and hydroxy;
8. Q is (c-10), X2 is preferably s or O, most preferably X2 is O;
R13 is preferably selected from hydrogen, C(1-3)alkyl and C(1-3)alkyloxy;
R14 is preferably hydrogen;
R15 is preferably selected from hydrogen, C(1-3)alkyl [wherein the alkyl moiety may be optionally substituted with Het1 (wherein Het1 is preferably morpholinyl)] and Het1 [wherein Het1 is preferably piperidinyl (wherein the thiazolyl moiety is optionally substituted with (Cxe2x95x90)R22) or thiazolyl {wherein the thiazolyl moiety is optionally substituted with C(1-3)alkyl (wherein the alkyl moiety is optionally substituted with NR23R24)}];
R22 is preferably C(1-3)alkyloxy;
R23 is preferably C(1-3)alkyl;
R24 is preferably C(1-3)alkyl;
or a N-oxide, addition salt, quaternary amine or stereochemically isomeric form thereof.
Particularly preferred compounds are those compounds of formula (I) wherein
B is a group of formula (b-2);
xe2x80x94A1xe2x95x90A2xe2x80x94A3xe2x95x90A4xe2x80x94 is a radical of formula (a-1);
groups R1, R2, R3 and R4 are hydrogen;
preferably m and n are 0 and p is 0 or 1;
D is Ar1 [wherein Ar1 is preferably phenylidene (wherein the phenylidene moiety may be optionally substituted with halo)];
L is Ar1 [wherein Ar1 is preferably phenyl {wherein the phenyl moiety may be optionally substituted with one or more substituents, preferably 1, 2 or 3 substituents, independently selected from halo, C(1-3)alkyloxy, C(1-3)alkyl, (SO2)R22 (wherein R22 is preferably C(1-3)alkyl (wherein the alkyl moiety may be optionally substituted with one or more halo), more preferably R22 is trifluoromethyl), NH(Cxe2x95x90O)R22 (wherein R22 is preferably 
xe2x80x83and Het1 [wherein Het1 is preferably pyridinyl or quinolinyl].
Q is most preferably is a bivalent radical of formula (c-1), (c-3), (c-4), (c-5), (c-7) or (c-10).
When
1. Q is (c-3), R5 is most preferably selected from hydrogen, hydroxy and cyano;
R6 is preferably selected from hydrogen, hydroxy, C(1-3)alkyl, C(1-3)alkyloxy and NR17R18;
R17 is preferably hydrogen;
R18 is preferably hydrogen;
2. Q is (c-4), R7 is preferably hydrogen;
3. Q is (c-5), R8 is preferably hydrogen;
4. Q is (c-7), R11 is preferably selected from hydroxy and C(1-3)alkyloxy [wherein the alkyloxy moiety is preferably substituted with (Cxe2x95x90O)R16];
R16 is preferably NR17R18;
R17 is preferably C(1-3)alkyl;
R18 is preferably C(3-6)cycloalkyl;
5. Q is (c-10), X2 is preferably O;
R13 is preferably selected from hydrogen and C(1-3)alkyl;
R14 is preferably hydrogen;
R15 is preferably selected from hydrogen and C(1-3)alkyl;
or a N-oxide, addition salt, quaternary amine or stereochemically isomeric form thereof.
Most preferred compounds include:
N-(4-benzolyphenyl)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
(B)-N-(4-benzolyphenyl)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
(E)-4,5-dihydro-N-[4-(hydroxyimino)phenylmethyl]phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide;
4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide;
[5S(B)]-4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide;
4,5-dihydro-N-[4-(phenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide;
N-[4-(aminophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
[5S(A)]-N-[4-(aminophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
N-[4-(cyanophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
4,5-dihydro-N-[4-(4-methoxybenzoyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide;
4,5-dihydro-N-[(4-(methoxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide;
4,5-dihydro-3-(3-pyridinyl)-N-[4-[[(2-pyridinylmethyl)amino]carbonyl]phenyl]-5-isoxazolecarboxamide;
(xc2x1)-[cyano-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]-phenyl]phenylmethyl] acetate;
(xc2x1)-(E)-4,5-dihydro-N-[4-(1-oxo-3-phenyl-2-propenyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide;
(xc2x1)-N-[4-(3,4-dimethoxybenzoyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
(xc2x1)-N-[4-(2,4-difluorobenzoyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
(xc2x1)-N-[4-(4,5-dihydro-1-methyl-3-phenyl-1H-pyrazol-5-yl)phenyl-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
(xc2x1)-N-[4-[(2,4-difluorophenyl)hydroxymethyl]phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide;
(B)-4,5-dihydro-3-(3-pyridinyl)-N-[4-(2-pyridinylcarbonyl)phenyl]-5-isoxazolecarboxamide;
(B2)-4,5-dihydro-N-[4-(hydroxy-2-pyridinylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide;
or a N-oxide, addition salt, the quaternary amine or stereochemically isomeric form thereof;
The present invention further includes the following processes for the preparation of a compound of formula (I) or stereoisomers, a N-oxide, a salt, a quaternary amine or a solvate thereof.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, for example, extraction, crystallization, distillation, trituration and chromatography.
In the following description, the symbols R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 , R18 , R19, R20, R21, R22, R23, R24, R25, B, D, Q, L, m, n, p and t have the meaning ascribed to them in formula (I) unless otherwise stated.
In order to simplify the structural representation of the compounds of formula (I), the group 
wherein xe2x80x94A1xe2x95x90A2xe2x80x94A3xe2x95x90A4xe2x80x94, R1 and q is as defined before, will hereinafter be represented by the symbol Z.
Compounds of formula (I) wherein B is formula (b-2), represented by formula (I-a) below, can generally be prepared by reacting an intermediate of formula (II) wherein W1 is C(1-3)alkyloxy, hydroxy or a halogen atom, with an appropriate reagent of formula (III). 
Said reaction can be performed in a reaction inert solvent, such as, chloroform, dichloroethane, dimethylformamide, tetrahydrofuran or a mixture thereof, and optionally in the presence of a suitable base, for example, N,N-dimethyl-pyridinamine or triethylamine. Convenient reaction temperatures range between 0xc2x0 C. and 100xc2x0 C.
Compounds of formula (III) can be obtained commercially or they can be made by methods well known in the art. Typically, compounds of formula (III) can be prepared by reacting a compound of formula HQxe2x80x94(C(1-3)alkyl)pxe2x80x94L with a compound of formula NO2xe2x80x94(C(1-3)alkyl)nxe2x80x94DW2 wherein W2 is a suitable leaving group, for example, a halogen atom. The nitro group can be converted in a amine by hydrogenation. Said reaction can be performed in a reaction inert solvent, such as, ethanol and in the presence of a suitable catalyst, such as palladium on carbon.
Intermediates of formula (II) wherein W1 is C(1-3)alkyloxy, said compound being represented by formula (II-a) below, can be prepared by cyclization. Said cyclization can be performed by reacting an intermediate of formula (IV) with a compound of formula 
in a reaction inert solvent such as, dichloroethane in the presence of a base such as, triethylamine. 
Intermediates of formula (IV) can be prepared by converting an aldehyde of formula (V) to an oxime of formula (VI), using art-known techniques, such as, using hydroxylamine hydrochloride in the presence of NaHCO3 or pyridine in a solvent, for example, ethanol. The oxime is subsequently reacted with Cl2(g). Said reaction can be performed in a solvent, for example, chloroform or a mixture thereof. Convenient reaction temperatures range between 0xc2x0 C. and room temperature. 
The intermediate of (II-a) can be conveniently converted into intermediates of formula (II) wherein W1 is OH, represented by formula (II-b), using a suitable base, for example, NaOH, in a solvent, for example methanol. The intermediate of (II-b) can subsequently be converted into intermediates of formula (II) wherein W1 is halo, represented by formula (II-c). A convenient procedure is converting the carboxylic acid group to the corresponding acid chloride atom using a suitable reagent such as, thionylchloride. 
Compounds of formula (I) wherein B is a bivalent radical (b-1), (b-2) or (b-3) can be prepared by a1,3-dipolar addition. Said addition reaction can be performed by reacting a compound of formula (IV) with an intermediate of formula 
wherein B is (b-1), (b-2) or (b-3).
The reaction can be performed in a reaction inert solvent, for example dichloroethane or dimethylformamide in the presence of a base such as, triethylamine or pyridine. Convenient reaction temperatures range between 0xc2x0 C. and 40xc2x0 C.
When B is (b-1), the intermediate of formula (VII) can be prepared by reacting a compound of formula 
with an intermediate formula 
The compounds of formula (VIII) an (IX) can be obtained commercially or made using methods known in the art. Typically, compounds of formula (IX) can be prepared by converting the cyano group of an intermediate of formula
CNxe2x80x94(C(1-3)alkyl)nxe2x80x94Dxe2x80x94Qxe2x80x94(C(1-3)alkyl)pxe2x80x94Lxe2x80x83xe2x80x83(X) 
to a carboxyl group using, for example, a combination of sulfuric and acetic acid in water, which in turn can be further reacted to an acyl halide using thionyl chloride.
Compounds of formula (X) can be prepared as in J. Am. Chem. Soc. (1981), 103(3), 634-640.
The intermediate of formula (VII), wherein B is (b-2), can be made by reacting the amine of formula (III), supra, with a compound of formula 
using methods known in the art.
Compounds of formula (VII) where B is (b-3) can be prepared by a two step substitution reactions as known in the art. Typically a compound of formula
w3xe2x80x94(C(1-3)alkyl)nxe2x80x94Dxe2x80x94Qxe2x80x94(C(1-3)alkyl)p-L, 
wherein W3 is a suitable leaving group such as a halogen atom can be reacted with a compound of formula (XI). Suitable solvents are tetrahydrofuran, benzene or dimethylacetamide or a mixture thereof. The reaction can be performed in the presence of suitable catalysts such as, for example, Zn/Cu and Pd complexes. Convenient reaction temperatures range between 0xc2x0 C. and 40xc2x0 C.
Compounds of formula (I) wherein B is a bivalent radical of formula (b-4), (b-5) or (b-6), can conveniently be prepared by cyclization of a compound of formula 
where E represents 
in paratoluene sulfonic acid and DMSO, at elevated temperature or where E represent 
in
POCl3 at elevated temperature.
Compounds of formula (XII) wherein E is (e-1) can be prepared by reacting an intermediate of formula 
with a compound of formula (II-c), supra. The reaction can be performed in a reaction inert solvent, such as dichloromethane, and in the presence of a suitable base, for example diisopropylethylamine. Convenient reaction temperatures range between 5xc2x0 C. and room temperature. Compounds of formula (XIII) can be prepared from a compound of formula (X), supra, by converting the cyano group to an amidoxime group using hydroxylamine hydrochloride using methods known in the art.
Compounds of formula (XII) wherein E is (e-3) can be prepared by reacting (II-c), supra, with a compound of formula 
Compounds of formula (XIV) can be prepared by reacting a compound of formula with N2H4 in a reaction inert solvent such as dichloromethane, in the presence of a suitable base, for example, N,N-dimethyl-pyridinamine or diisopropylethaneamine.
Compounds of formula (XII) wherein E is (e-2) can be prepared by reacting a compound of formula (XVI) with an intermediate of formula (IX). The reaction can be performed in a reaction inert solvent, such as dichloromethane, and in the presence of a suitable base, for example diisopropylethylamine. Convenient reaction temperatures range between 0xc2x0 C. and room temperature.
Compounds of formula (XVI) can be prepared from a nitrile derivative of formula (XV) by converting the cyano group to an amidoxime group using hydroxylamine hydrochloride or a functional derivative thereof using methods known in the art. 
Compounds of formula (XV) can be prepared by reacting an amidoxime of formula (VI) with 1-chloro-2,5-pyrrolidinedione and a compound of formula
xe2x95x90(C(1-3)alkyl)nxe2x80x94CN 
in a reaction inert solvent such as chloroform and in the presence of a suitable base, for example, pyridine, triethylamine or a mixture thereof.
Compounds of formula (I) wherein Q is a bivalent radical of formula (c-1), can generally be prepared by reacting an intermediate of formula (XVII) wherein W4 is a suitable leaving group, for example, a halogen atom, with a compound of formula (XVIII). Said reaction can be performed in a reaction-inert solvent, for example, dichloroethane, preferably in the presence of a catalyst such as a trifurylphosphine-palladium (0) complex. The reaction is performed at an elevated temperature, ranging between 80xc2x0 C. and 100xc2x0 C. 
Intermediates of formula (XVII) can be obtained commercially or prepared by methods known in the art.
Intermediates of formula (XVIII) can be prepared by reacting a compound of formula (XIX), wherein W5 is a suitable leaving group, for example, a halogen atom, with Sn2(CH3)6. The reaction can be performed in a reaction inert solvent such as dioxane and in the presence of a suitable catalyst such as a Pd-complex. The reaction is performed at an elevated temperature, ranging between 80xc2x0 C. and 100xc2x0 C. 
Compounds of formula (XIX) can be prepared by reacting compounds of formula (II-c) supra, with compounds of formula
H2Nxe2x80x94(C(1-3)alkyl)nxe2x80x94Dxe2x80x94W5. 
These compounds can be obtained commercially or prepared by methods known in the art.
Compounds of formula (I) wherein Q is of formula (c-5), (c-8) or (c-9) can conveniently be prepared by reacting an intermediate of formula 
wherein W6 is, for example, hydroxy or a halogen atom, with an appropriate functional primary or secondary amine derivative; For example, reacting with amines, such as 
in a reaction inert solvent, for example, dichloromethane, dimethylformamide or a mixture thereof and in the presence of a suitable base such as diisopropylethylamine or triethylamine. Convenient reaction temperatures range between 0xc2x0 C. and 50xc2x0 C.
Compounds of formula (XX) can be prepared by reacting a compound of formula (II-c) supra, with a compound of formula
H2Nxe2x80x94(C(1-3)alkyl)nxe2x80x94Dxe2x80x94COOH, 
in a reaction inert solvent, such as, chloroform, dichloroethane, dimethylformamide, tetrahydrofuran or a mixture thereof, and optionally in the presence of a suitable base, for example, N,N-dimethyl-pyridinamine or triethylamine. Convenient reaction temperatures range between 0xc2x0 C. and 100xc2x0 C.
The resulting acid can subsequently be converted into a compound of formula (XX) using standard techniques.
Where necessary or desired, any one or more of the following further steps in any order may be performed:
(i) removing any remaining protecting group(s);
(ii) converting a compound of formula (I) or a protected form thereof into a further compound of formula (I) or a protected form thereof
(iii) converting a compound of formula (I) or a protected form thereof into a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof;
(iv) converting a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof into a compound of formula (I) or a protected form thereof;
(v) converting a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof into another N-oxide, a pharmaceutically acceptable addition salt a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof;
(vi) where the compound of formula (I) is obtained as a mixture of (R) and (S) enantiomers resolving the mixture to obtain the desired enantiomer.
Compounds of formula (I), N-oxides, addition salts, quaternary amines and stereochemical isomeric forms thereof can be converted into further compounds according to the invention using procedures known in the art, for example:
A.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3) and R5 is OH and R6 is H, by reduction of the corresponding compound of formula (I), wherein Q is a radical of formula (c-1). The reaction is carried out in the presence of a suitable reducing agent, for example, sodiumborohydride in a suitable solvent, for example, water, an alcohol, tetrahydrofuran or a mixture thereof.
B.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is OH and R6 is as defined in formula (I), by reacting the corresponding compound of formula (I), wherein Q is a radical of formula (c-1), with a compound of formula X-R6, wherein X is halo and R6 is as defined in formula (I), Said reaction is typically performed in a reaction inert solvent, for example, tetrahydrofuran, and in the presence of Mg. When X is Br, the reaction may conveniently be carried out in the presence of butyl lithium.
C) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is C(1-6)alkyloxy and R6 is as defined in formula (I), by treating the corresponding compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is OH and R6 is as defined in formula (I), using a suitable alkylating agent according to methods well known in the art.
D.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is NR17R18 where R17 and R18 are as defined in formula (I), by reacting a compound of formula 
where W7 is a leaving group such as, halo, OSO2CH3 or OSO2CF3, with an appropriate amine, for example, NHR17R18, in a reaction inert solvent, for example dimethylformamide and in the presence of a suitable base, such as, triethylamine. Compounds of formula (XXI) can be prepared from a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is OH and R6 is as defined in formula (I), by methods known in the chemical literature or well known to a skilled person.
E.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is NH2, by reacting a compound of formula (XXI) with a salt of a compound of formula 
followed by an acid deprotection using trifluoroacetic acid. The reaction can be performed in a reaction inert solvent such as tetrahydrofuran or dichloromethane.
F.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is NHR18 where R18 is (C=O)R19 or (SO2)R19, by reacting the corresponding amino compound described in E.) above with a compound of formula W8xe2x88x92R18, where W8 is a suitable leaving group, such as, halo and R18 is (C=O)R19 or (SO2)R19.
G.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is NHR18 where R18 is (C=O)CH2R19 and R19 is NR20R21, by reacting the corresponding compound of formula (I) wherein R18 is a group (C=O)CH2-halo with HNR20R21 in a reaction inert solvent, for example, tetrahydrofuran, dichloromethane, dimethylformamide or a mixture thereof.
H.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is NHR18 where R18 is (C=O)R19 and R19 is NHR21, by reacting a corresponding compound wherein R5 is NH2 with a compound of formula R21N=C=O in a suitable solvent, for example, tetrahydrofuran, dioxan, acetonitrile or a mixture thereof.
I.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c=10) and X2 is O, by reacting a compound of formula 
with HNR17R18, in a reaction-inert solvent, for example, tetrahydrofuran, dichloromethane, dimethylformamide or a mixture thereof, preferably in the presence of a suitable base such as, for example diisopropylethylamine or triethylamine.
Compounds of formula (XXIII) can be prepared from a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is cyano and R6 is as defined in formula (I), by methods known in the chemical literature or well known to a skilled person.
J.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-6), where R9 and R10 are H, by reacting the corresponding compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is OH and R6 is methyl with methylsulfonylchloride in the presence of a suitable base, such as, triethylamine, in a reaction inert solvent, for example, dichloromethane.
K.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is hydroxy and R6 is C(1-6)alkynyl, by reacting the corresponding compound of formula (I) wherein Q is a radical of formula (c-1) with a suitable reagent, such as, Na+xe2x88x92Cxe2x89xa1C(1-5)alkyl, in a reaction inert solvent, for example, tetrahydrofuran.
L.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 and R6 together form 1,3-dioxalanyl, by reacting the corresponding compound of formula (I) wherein Q is a radical of formula (c-1) with 1,2-ethanediol in the presence of 
and a reaction inert solvent, for example, toluene.
M.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is O(C=O)NH2, by reacting the corresponding compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is hydroxy and R6 is as defined in formula (I) with chlorosulfonyl isocyanate, in a reaction inert solvent, for example , dichloromethane.
N.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-10) wherein X2 is S and R14 and R15 are H, by reacting a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is cyano, with H2S in the presence of a suitable base, such as, pyridine, triethylamine or a mixture thereof.
O.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is C(1-6)alkyloxy and R6 is as defined in formula (I), by reacting a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is a halogen atom or other R5 substituent which acts as a leaving group and R6 is as defined in formula (I), with the corresponding hydroxyC(1-6)alkyl.
P.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is N3 and R6 is as defined in formula (I), by reacting a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is O(C=O)C(1-6)alkyl with (CH3)3SiN3 in a reaction inert solvent such as dichloromethane in the presence of SnCl4. The latter compound of formula (I) wherein R5 is O(C=O)C(1-6)alkyl can be prepared from the corresponding compound of formula (I) wherein R5 is hydroxy, using acetic anhydride, in the presence of a suitable base, for example, pyridine.
Q.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c-3), where R5 is OC(1-6)alkylOC(1-6)alkyl and R6 is as defined in formula (I), by reacting a compound of formula (I) wherein Q is a radical of formula (c-3), where R6 is as defined in formula (I) and R5 is OSi(CH3)3, with W9C(1-6)alkylOC(1-6)alkyl, wherein W9 is a suitable leaving group, for example, a halogen atom. The reaction can be performed in a reaction inert solvent such as chloroform in the presence of P2O5. The latter compound of formula (I) where R5 is OSi(CH3)3 can be prepared from the corresponding compound of formula (I) wherein Q is a radical of formula (c-1), using (CH3)3SiR6.
R.) Compounds of formula (I) wherein Q is a radical of formula (c3), where R6 is Het1 and R5 is as defined in formula (I), by cyclization of the corresponding compound of formula (I), wherein Q is a radical of formula (c3), where R5 is CN and R6 is azydyl. Said cyclization is performed in a reaction inert solvent such as tetrahydrofuran, methanol or mixture thereof and in the presence of a suitable reducing agent such as NaBH4.
S.) Compounds of formula (I) where Q is a radical of formula (c3), wherein R5 is CN and R6 is C1-6 alkyloxycarbonyloxy, by reacting the corresponding compound of formula (I), wherein Q is a radical of formula (c3), where R5 is CN and R6 is OH, using a compound of formula; 
wherein W10 is a leaving group such as, halo, OSO2CH3 or OSO2CF3 in the presence of a suitable base, such as, triethylamine, in a reaction inert solvent for example dicloromethane.
T.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c3), where R5 is as defined in formula (I) and R6 is hydroxy C(1-6)alkyl, by reacting a compound of formula (I) wherein Q is a radical of formula (c3), where R5 is as defined in formula (I) and R6 is C(1-6)alkyl O C(1-6)alkyl where the alkyloxy moiety may be optionally substituted by one or more substituents as defined in formula (I), with a hydrolizing agent such as HCl in a reaction inert solvent such as 1,4-dioxane.
U.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c3), where R5 is as defined in formula (I) and R6 is hydroxy C(1-6)alkyl, by reacting a compound of formula (I) wherein Q is a radical of formula (c3), where R5 is as defined in formula (I) and R6 is hydrogen, with (CH2O)n using Triton B in the presence of a suitable base, for example pyridine.
V.) Preparation of a compound of formula (I) wherein Q is a radical of formula (c10), wherein X2 is O and R14 and R15 are as defined in formula (I), where R13 is Het1, by reacting the corresponding compound of formula 
Wherein W11 is a leaving group for example halo, with an appropriate amine such as NHR17R18.
It will be appreciated by those skilled in the art that in the processes described above the functional groups of intermediate compounds may need to be blocked by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C(1-6)alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after a reaction step.
The use of protecting groups is fully described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J W F McOmie, Plenum Press (1973), and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 2nd edition, T W Greene and P G M Wutz, Wiley Interscience (1991).
Additionally, the N-atoms in compounds of formula (I) can be methylated by art-known methods using CH3-I in a suitable solvent such as, for example 2propanone, tetrahydrofuran or dimethylformamide.
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation of which some examples are mentioned hereinabove.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter-current distribution, liquid chromatography and the like.
Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diasteromeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
Some of the intermediates and starting materials as used in the reaction procedures mentioned hereinabove are known compounds and may be commercially available or may be prepared according to art-known procedures.
The compounds of the present invention are useful because they possess pharmacological properties. They can therefore be used as medicines.
The growth inhibitory effect of the present compounds has been demonstrated by in vitro proliferation assays on human phytohemagglutinin stimulated white blood of which the test results for growth inhibition are presented in the experimental part hereinafter. Growth inhibition was also demonstrated in vitro on human keratinocytes.
Accordingly, the present invention provides the compounds of formula (I) and their pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms for use in therapy. More particular in the treatment or prevention of T cell mediated diseases. The compounds of formula (I) and their pharmaceutically acceptable N-oxides, addition salts, quaternary amines and the stereochemically isomeric forms may hereinafter be referred to as compounds according to the invention.
Disorders for which the compounds according to the invention are particularly useful are rheumatic diseases like rheumatoid arthritis, juvenile arthritis and osteoarthritis; systemic inflammatory disease like systemic lupus erythematosis; psoriasis and psoriatic arthritis; T cell leukemia; transplant rejection and graft-versus-host disease.
Other therapeutic uses (particularly human therapeutic uses) for the compounds of formula (I) and their pharmaceutically acceptable salts and solvates include the treatment of conditions outlined in table 1.
In view of the utility of the compounds according to the invention, there is provided a method for the treatment of an animal, for example, a mammal including humans, suffering from T cell mediated diseases, in particular T cell blast mediated disorders such as rheumatic diseases like rheumatoid arthritis, juvenile arthritis and osteoarthritis; systemic inflammatory disease like systemic lupus erythematosis; psoriasis and psoriatic arthritis; T cell leukeamia; transplant rejection and graft-versus-host disease, which comprises administering an effective amount of a compound according to the present invention.
Said method comprising the systemic or topical administration of an effective amount of a compound according to the invention, to warm-blooded animals, including humans.
In yet a further aspect, the present invention provides the use of the compounds according to the invention in the manufacture of a medicament for treating any of the aforementioned T cell mediated diseases or indications.
The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutical effect will be, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A suitable daily dose would be from 0.01 mg/kg to 50 mg/kg body weight, in particular from 0.05 mg/kg to 10 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington""s Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclodextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.
Appropriate cyclodextrins are xcex1-, xcex2- or xcex3-cyclodextrins or ethers and mixed ethers thereof
wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C(1-6)alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated xcex2-CD; hydroxy C(1-6)alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy C(1-6)alkyl, particularly carboxymethyl or carboxyethyl; C(1-6)alkylcarbonyl, particularly acetyl; C(1-6)alkyloxycarbonyl C(1-6)alkyl or carboxy-C(1-6)alkyloxy C(1-6)alkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; C(1-6)alkylcarbonyloxy C(1-6)alkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are xcex2-CD, randomly methylated xcex2-CD, 2,6-dimethyl-xcex2-CD, 2-hydroxyethyl-xcex2-CD, 2-hydroxyethyl-xcex3-CD, 2-hydroxypropyl-xcex3-CD and (2-carboxymethoxy)propyl-xcex2-CD, and in particular 2-hydroxypropyl-xcex2-CD (2-HP-xcex2-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The M.S. value can be determined by various analytical techniques, preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10.
The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The D.S. value can be determined by various analytical techniques, preferably, as measured by mass spectrometry, the D.S. ranges from 0.125 to 3.
Hereinafter, the term xe2x80x98RTxe2x80x99 means room temperature, xe2x80x98THFxe2x80x99 means tetrahydrofuran, xe2x80x98EtOAcxe2x80x99 means ethylacetate, xe2x80x98DMFxe2x80x99 means N,N-dimethylformamide, xe2x80x98DIPExe2x80x99 means diisopropylether, xe2x80x98Et2Oxe2x80x99 means diethylether, xe2x80x98NH4OAcxe2x80x99 means amoniumacetate and xe2x80x98HOAcxe2x80x99 means acetic acid.